Early detection of breast cancer and new treatments have now put the 5 year survival rate of patients above 99% and virtually all breast cancer deaths are the result of distal metastases, thus preventing metastasis and recurrence is of great clinical importance. The overall goal of this work is to address whether sympathetic nervous system (SNS) activation induced by chronic stress or depression in breast cancer patients contributes to bone metastasis, recurrence and survival. Clinical evidence and experimental data accumulated in our laboratory, using two mouse models of cancer metastasis to bone, support this hypothesis. Our data also point to osteoblast-derived cytokines RANKL and IL6 as a crucial factor promoting the colonization of cancer cells in the bone microenvironment in response to SNS activation, in addition to their effect on osteoclastogenesis and osteolysis. We propose in this application to characterize the cellular and molecular mechanisms underlying these SNS effects (Aim 1 and 2) and to address whether -blockers and RANKL blockade have beneficial effects on bone metastasis and survival in preclinical mouse models characterized by endogenous sympathetic activation (Aim 3).